A new program has been initiated in the IRP of the NIA to investigate molecular changes associated with brain aging and Alzheimer's disease. The unit has four major areas of focus: molecular neuropathology, mechanisms of cell death, neurotrophic factors, and molecular biomarkers of Alzheimer's disease. Molecular neuropathology includes studies of aberrant proteolysis of the amyloid precursor protein and amyloid deposition in Alzheimer's disease, differential regulation of tau gene expression in Alzheimer's disease, and creation of animal models which mimic the neuropathology of the disease. Mechanisms of cell death includes studies of the structure and regulation of excitatory amino acid receptors and the role of calcium metabolism in neuronal cell death. Neurotrophic factors includes the characterization of novel growth factors and their receptors in the central nervous system, the role of decreased trophic support in neuronal atrophy and death, and studies of trophic activity in extracts of Alzheimer's tissue. Molecular biomarkers of Alzheimer's disease is directed towards the identification of early molecular changes in tissue biopsies obtained from patients in the Baltimore Longitudinal Study of Aging (BLSA), and changes in gene expression in familial Alzheimer's disease pedigrees assayed from cell lines maintained by the NIA.